Clinical Trials with Alteplase (RT-pa) in Acute Myocardial Infarction

Abstract

Alteplase (recombinant human tissue plasminogen activator, rt-PA) first became available for clinical trials in acute myocardial infarction in 1984 (1). At this time there was already considerable experience with thrombolysis using intracoronary streptokinase (2), and a consensus that the benefits of coronary thrombolysis operated through the early restoration of coronary patency. The potential benefits of rt-PA compared with streptokinase as seen in 1984 are listed in table 1 —the principal hope being that a “thrombus specific” agent such as rt-PA would provide more effective and rapid thrombolysis with a minimum of bleeding complications. The endpoint in the earliest trials (TIMI 1 and ECSG 1) was angiographic coronary patency — the “hardest” endpoint realistically attainable with the limited amounts of rt-PA then available. The results of these studies were favourable to rt-PA in comparison both with placebo (ECSG-1) and streptokinase (ECSG-2 and TIMI-1) but it was clear that larger studies would be needed both to provide adequate safety data for registration, and to provide more clearcut evidence concerning “outcome” measurements such as mortality and left ventricular function. Moreover the TIMI-1 study had raised a worry concerning the apparent high rate of reocclusion following rt-PA thrombolysis (3,4). The question of reocclusion was specifically addressed in ECSG-3, with reassuring results. Nevertheless, concern about reocclusion undoubtedly influenced subsequent trials both in terms of the use of a prolonged rt-PA infusion and a feeling that results might be further improved by combining thrombolysis with early angioplasty.